Since the rate of progression to AIDS correlates directly with the level of plasma viremia, changes in viral transcriptional rates directly affect HIV pathogenesis. We identified and cloned a human cDNA encoding a new cytokine, SDF-1gamma, a previously unrecognized splice variant of the SDF1 gene. SDF-1gamma contains a domain that is highly homologous to the basic domain of Tat, the HIV transactivator. Our preliminary data show that SDF-1gamma inhibits Tat-dependent HIV transcription. We hypothesize that SDF-1gamma suppresses HIV replication by competing with Tat for TAR binding. To test this hypothesis, we will develop reagents to detect SDF-1gamma protein and mRNA and use them to measure SDF-1gamma levels in different tissues and in response to immune activation signals and HIV infection. We will purify recombinant SDF-1gamma and test its biological properties, mainly antiviral and chemotactic activities. To determine how SDF-1gamma inhibits Tat transactivation, we will test its ability to bind to the HIV TAR element and to compete for binding with the transactivator Tat. To determine which domains of SDF-1gamma are critical for the inhibition of HIV transactivation, we will conduct a mutational analysis of the SDF-1gamma open reading frame. In addition, we will determine whether SDF-1gamma inhibits transcription in the cell where it is produced (i.e., an in cis effect) or whether SDF-1gamma is secreted and migrates to another cell to inhibit transcription (i.e., an in trans effect). Finally, we will test the possibility that SDF-1gamma accounts for all or part of the activity ascribed to the CD8+ T-cell antiviral factor (CAF), which has been reported to specifically inhibit HIV transcription.